1. ¹Department of Pharmacology and MRCCMT, Busan 604-714, South Korea
2. ²Department of Radiology, Busan 604-714, South Korea
3. ³Department of Hemato-oncology, Busan 604-714, South Korea
4. ⁴Department of Pathology, Busan 604-714, South Korea
5. ⁵Department of Uro-oncology, Dong-A University Medical College, Busan 604-714, South Korea
6. ⁶Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
7. ⁷Jennerex Biotherapeutics, Inc., Mill Valley, CA 94941, USA
8. ⁸Clinical Pharmacology, University of Oxford, Oxford OX1 2JD, UK

Correspondence: T. H. Hwang, E-mail: thhwang@dau.ac.kr

Received 9 March 2006; Revised 16 May 2006; Accepted 16 May 2006.

Abstract

Targeted oncolytic viruses and immunostimulatory therapeutics are being developed as novel cancer treatment platforms. These approaches can be combined through the expression of immunostimulatory cytokines from targeted viruses, including adenoviruses and herpesviruses. Although intratumoral injection of such viruses has been associated with tumor growth inhibition, eradication of distant metastases was not reported. The major limitations for this approach to date have been (1) inefficient intravenous virus delivery to tumors and (2) the lack of predictive, immunocompetent preclinical models. To overcome these hurdles, we developed JX-594, a targeted, thymidine kinase^- vaccinia virus expressing human GM-CSF (hGM-CSF), for intravenous (i.v.) delivery. We evaluated two immunocompetent liver tumor models: a rabbit model with reproducible, time-dependent metastases to the lungs and a carcinogen-induced rat liver cancer model. Intravenous JX-594 was well tolerated and had highly significant efficacy, including complete responses, against intrahepatic primary tumors in both models. In addition, whereas lung metastases developed in all control rabbits, none of the i.v. JX-594-treated rabbits developed detectable metastases. Tumor-specific virus replication and gene expression, systemically detectable levels of hGM-CSF, and tumor-infiltrating CTLs were also demonstrated. JX-594 holds promise as an i.v.-delivered, targeted virotherapeutic. These two tumor models hold promise for the optimization of this approach.